
Polymorphisms in the il12b gene affect structure and expression of il-12 in nod and other autoimmune-prone mouse strains
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ABSTRACT Interleukin (Il)-12 is a heterodimeric cytokine composed of 35 and 40 kD chains that plays a key role in the induction of Th1 cells, a T cell subset involved in many autoimmune
diseases. We report here the cDNA sequence encoding the IL-12 p40 subunit from the autoimmune-prone non-obese diabetic (NOD) mouse, which spontaneously develops type 1 diabetes. Compared
with the C57BL/6 sequence, there are two base changes that lead to amino acid replacements. Other autoimmune-prone strains, but not the diabetes-resistant NOR strain, share the same allele
as NOD. We found both trans- and cis- allele-dependent effects on levels of basal and induced IL-12p40 expression. Furthermore, we show that one of these changes results in a structural
change in the p40 molecule, as evidenced by the failure of a monoclonal antibody to bind NOD IL-12. These findings have implications for the predisposition to autoimmune responses in NOD and
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August 2024 REFERENCES * Gately MK, Renzetti LM, Magram J, Stern AS, Gubler U, Presky DH . The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses
_Ann Rev Immunol_ 1998 16: 495–521 Article CAS Google Scholar * Trembleau S, Germann T, Gately MK, Adorini L . The role of IL-12 in the induction of organ-specific autoimmune diseases
_Immunol Today_ 1995 16: 383–386 Article CAS Google Scholar * Schoenhaut DS, Chua AO, Wolitzky AG _et al_. Cloning and expression of murine IL-12 _J Immunol_ 1992 148: 3433–3440 CAS
Google Scholar * Gearing DP, Cosman D . Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor _Cell_ 1991
66: 9–10 Article CAS Google Scholar * Heinzel FP, Rerko MR, Ling P, Hakimi J, Schoenhaut DS . Interleukin-12 is produced _in vivo_ during endotoxemia and stimulates synthesis of gamma
interferon _Infect Immun_ 1994 62: 4244–4249 CAS PubMed PubMed Central Google Scholar * Wysocka M, Kubin M, Vieira LQ _et al_. Interleukin-12 is required for interferon-gamma production
and lethality in lipopolysaccharide-induced shock in mice _Eur J Immunol_ 1995 25: 672–676 Article CAS Google Scholar * Presky DH, Minetti LJ, Gillessen S _et al_. Evidence for multiple
sites of interaction between IL-12 and its receptor _Ann NY Acad Sci_ 1996 795: 390–393 Article CAS Google Scholar * Gillessen S, Carvajal D, Ling P _et al_. Mouse interleukin-12 (IL-12)
p40 homodimer: a potent IL-12 antagonist _Eur J Immunol_ 1995 25: 200–206 Article CAS Google Scholar * Mattner F, Fischer S, Guckes S _et al_. The interleukin-12 subunit p40 specifically
inhibits effects of the interleukin-12 heterodimer _Eur J Immunol_ 1993 23: 2202–2208 Article CAS Google Scholar * Huang D, Cancilla M, Morahan G . Complete primary structure, chromosomal
localisation, and definition of polymorphisms of the gene encoding the human IL12 p40 subunit _Genes Immun_ 2000 1: 515–520 Article CAS Google Scholar * Morahan G, Huang D, Ymer SI _et
al_. Linkage disequilibrium of type 1 diabetes with _IL12B_ regulatory alleles _Nat Genet_ 2001 27: 218–221 Article CAS Google Scholar * Yoshida K, Kikutani H . Genetic and immunological
basis of autoimmune diabetes in the NOD mouse _Rev Immunogenet_ 2000 2: 140–146 CAS PubMed Google Scholar * Rothe H, Burkart V, Faust A, Kolb H . Interleukin-12 gene expression is
associated with rapid development of diabetes mellitus in non-obese diabetic mice _Diabetologia_ 1996 39: 119–122 CAS PubMed Google Scholar * Tone Y _et al_. Structure and chromosomal
location of the mouse interleukin-12 p35 and p40 subunit genes _Eur J Immunol_ 1996 26: 1222–1227 Article CAS Google Scholar * Chirgwin JM, Pzybla AE, MacDonald FJ, Rutter WJ . Isolation
of biologically active ribonucleic acid from sources enriched in ribonuclease _Biochemistry_ 1979 18: 5294–5299 Article CAS Google Scholar * McClive P, Baxter A, Morahan G . Genetic
polymorphisms of the non-obese diabetic (NOD) mouse _Immunol Cell Biol_ 1994 72: 137–142 Article CAS Google Scholar * Courtenay JS, Dallman MJ, Dayan AD, Martin A, Mosedale B .
Immunization against heterologous type II collagen induces arthritis in mice _Nature_ 1980 282: 666–668 Article Google Scholar * Serreze D, Prochazka M, Reifsnyder P, Bridgett M, Leiter E
. Use of recombinant congenic and congenic strains of NOD mice to identify a new insulin-dependent diabetes resistance gene _J Exp Med_ 1994 180: 1553–1558 Article CAS Google Scholar *
Todd JA, Aitman TJ, Cornall RJ _et al_. Genetic analysis of autoimmune Type 1 diabetes mellitus in mice _Nature_ 1991 351: 542–547 Article CAS Google Scholar * Morahan G, McClive P, Huang
D, Little P, Baxter A . Genetic and physiological association of diabetes susceptibility with raised Na+/H+ exchange activity _Proc Natl Acad Sci_ 1994 91: 5898–5902 Article CAS Google
Scholar * Trembleau S, Penna G, Gregori S, Gately MK, Adorini L . Deviation of pancreas-infiltrating cells to Th2 by interleukin-12 antagonist administration inhibits autoimmune diabetes
_Eur J Immunol_ 1997 27: 2230–2239 Article Google Scholar * Rothe H, O’Hara RM Jr, Martin S, Kolb H . Suppression of cyclophosphamide induced diabetes development and pancreatic Th1
reactivity in NOD mice treated with the interleukin (IL)-12 antagonist IL-12(p40)2 _Diabetologia_ 1997 40: 641–646 Article CAS Google Scholar * Alleva DG, Pavlovich RP, Grant C, Kaser SB,
Beller DI . Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains: elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-alpha
and IL-10 define a unique cytokine profile in macrophages from young nonobese diabetic mice _Diabetes_ 2000 49: 1106–1115 Article CAS Google Scholar * Alleva DG, Johnson EB, Wilson J,
Beller DI, Conlon PJ . SJL and NOD macrophages are uniquely characterized by genetically programmed, elevated expression of the IL-12(p40) gene, suggesting a conserved pathway for the
induction of organ-specific autoimmunity _J Leukoc Biol_ 2001 69: 440–448 CAS PubMed Google Scholar * Trembleau S, Penna G, Gregori S, Magistrelli G, Isacchi A, Adorini L . Early Th1
response in unprimed nonobese diabetic mice to the tyrosine phosphatase-like insulinoma-associated protein 2, an autoantigen in type 1 diabetes _J Immunol_ 2000 165: 6748–6755 Article CAS
Google Scholar * Gately MK, Chizzonite R, Presky DH . Measurement of human and mouse IL-12 _Curr Protocols Immunol_ 1995 3: 15:6.16.1 Google Scholar * Yoon C, Johnston SC, Tang J, Stahk M,
Tobin JF, Somers WS . Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-1 _Embo J_ 2000 19: 3530–3541 Article CAS Google Scholar *
Hansen JE, Lund O, Tolstrup N, Gooley AA, Williams KL, Brunak S . NetOglyc: prediction of mucin type O-glycosylation sites based on sequence context and surface accessibility _Glycoconjugate
J_ 1998 15: 115–130 Article CAS Google Scholar Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * The Walter and Eliza Hall Institute of Medical Research, PO Royal
Melbourne Hospital, Victoria, 3050, Australia S I Ymer, D Huang, K Branson & G Morahan * Roche Milano Ricerche, Via Olgettina 58, Milano, 20132, Italy G Penna, S Gregori & L Adorini
Authors * S I Ymer View author publications You can also search for this author inPubMed Google Scholar * D Huang View author publications You can also search for this author inPubMed Google
Scholar * G Penna View author publications You can also search for this author inPubMed Google Scholar * S Gregori View author publications You can also search for this author inPubMed
Google Scholar * K Branson View author publications You can also search for this author inPubMed Google Scholar * L Adorini View author publications You can also search for this author
inPubMed Google Scholar * G Morahan View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to G Morahan. ADDITIONAL
INFORMATION This work was supported by the National Health and Medical Research Council of Australia, by a special Diabetes Interdisciplinary Research Program grant from the NHMRC-Juvenile
Diabetes Foundation International and by the CRC for Discovery of Genes for Common Human Diseases. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Ymer,
S., Huang, D., Penna, G. _et al._ Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains. _Genes Immun_ 3, 151–157 (2002).
https://doi.org/10.1038/sj.gene.6363849 Download citation * Received: 20 November 2001 * Accepted: 02 December 2001 * Published: 21 May 2002 * Issue Date: 01 May 2002 * DOI:
https://doi.org/10.1038/sj.gene.6363849 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not
currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * IL12b * autoimmunity * immunogenetics * genetic
regulation * epitope